Cargando…

Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa

Synaptic loss, neuronal death, and circuit remodeling are common features of central nervous system neurodegenerative disorders. Retinitis pigmentosa (RP), the leading cause of inherited blindness, is a group of retinal dystrophies characterized by photoreceptor dysfunction and death. The insulin re...

Descripción completa

Detalles Bibliográficos
Autores principales: Sánchez-Cruz, Alonso, Hernández-Pinto, Alberto, Lillo, Concepción, Isiegas, Carolina, Marchena, Miguel, Lizasoain, Ignacio, Bosch, Fátima, de la Villa, Pedro, Hernández-Sánchez, Catalina, de la Rosa, Enrique J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021205/
https://www.ncbi.nlm.nih.gov/pubmed/35444190
http://dx.doi.org/10.1038/s41419-022-04839-0
_version_ 1784689754496827392
author Sánchez-Cruz, Alonso
Hernández-Pinto, Alberto
Lillo, Concepción
Isiegas, Carolina
Marchena, Miguel
Lizasoain, Ignacio
Bosch, Fátima
de la Villa, Pedro
Hernández-Sánchez, Catalina
de la Rosa, Enrique J.
author_facet Sánchez-Cruz, Alonso
Hernández-Pinto, Alberto
Lillo, Concepción
Isiegas, Carolina
Marchena, Miguel
Lizasoain, Ignacio
Bosch, Fátima
de la Villa, Pedro
Hernández-Sánchez, Catalina
de la Rosa, Enrique J.
author_sort Sánchez-Cruz, Alonso
collection PubMed
description Synaptic loss, neuronal death, and circuit remodeling are common features of central nervous system neurodegenerative disorders. Retinitis pigmentosa (RP), the leading cause of inherited blindness, is a group of retinal dystrophies characterized by photoreceptor dysfunction and death. The insulin receptor, a key controller of metabolism, also regulates neuronal survival and synaptic formation, maintenance, and activity. Indeed, deficient insulin receptor signaling has been implicated in several brain neurodegenerative pathologies. We present evidence linking impaired insulin receptor signaling with RP. We describe a selective decrease in the levels of the insulin receptor and its downstream effector phospho-S6 in retinal horizontal cell terminals in the rd10 mouse model of RP, as well as aberrant synapses between rod photoreceptors and the postsynaptic terminals of horizontal and bipolar cells. A gene therapy strategy to induce sustained proinsulin, the insulin precursor, production restored retinal insulin receptor signaling, by increasing S6 phosphorylation, without peripheral metabolic consequences. Moreover, proinsulin preserved photoreceptor synaptic connectivity and prolonged visual function in electroretinogram and optomotor tests. These findings point to a disease-modifying role of insulin receptor and support the therapeutic potential of proinsulin in retinitis pigmentosa.
format Online
Article
Text
id pubmed-9021205
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-90212052022-04-28 Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa Sánchez-Cruz, Alonso Hernández-Pinto, Alberto Lillo, Concepción Isiegas, Carolina Marchena, Miguel Lizasoain, Ignacio Bosch, Fátima de la Villa, Pedro Hernández-Sánchez, Catalina de la Rosa, Enrique J. Cell Death Dis Article Synaptic loss, neuronal death, and circuit remodeling are common features of central nervous system neurodegenerative disorders. Retinitis pigmentosa (RP), the leading cause of inherited blindness, is a group of retinal dystrophies characterized by photoreceptor dysfunction and death. The insulin receptor, a key controller of metabolism, also regulates neuronal survival and synaptic formation, maintenance, and activity. Indeed, deficient insulin receptor signaling has been implicated in several brain neurodegenerative pathologies. We present evidence linking impaired insulin receptor signaling with RP. We describe a selective decrease in the levels of the insulin receptor and its downstream effector phospho-S6 in retinal horizontal cell terminals in the rd10 mouse model of RP, as well as aberrant synapses between rod photoreceptors and the postsynaptic terminals of horizontal and bipolar cells. A gene therapy strategy to induce sustained proinsulin, the insulin precursor, production restored retinal insulin receptor signaling, by increasing S6 phosphorylation, without peripheral metabolic consequences. Moreover, proinsulin preserved photoreceptor synaptic connectivity and prolonged visual function in electroretinogram and optomotor tests. These findings point to a disease-modifying role of insulin receptor and support the therapeutic potential of proinsulin in retinitis pigmentosa. Nature Publishing Group UK 2022-04-20 /pmc/articles/PMC9021205/ /pubmed/35444190 http://dx.doi.org/10.1038/s41419-022-04839-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sánchez-Cruz, Alonso
Hernández-Pinto, Alberto
Lillo, Concepción
Isiegas, Carolina
Marchena, Miguel
Lizasoain, Ignacio
Bosch, Fátima
de la Villa, Pedro
Hernández-Sánchez, Catalina
de la Rosa, Enrique J.
Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa
title Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa
title_full Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa
title_fullStr Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa
title_full_unstemmed Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa
title_short Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa
title_sort insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021205/
https://www.ncbi.nlm.nih.gov/pubmed/35444190
http://dx.doi.org/10.1038/s41419-022-04839-0
work_keys_str_mv AT sanchezcruzalonso insulinreceptoractivationbyproinsulinpreservessynapsesandvisioninretinitispigmentosa
AT hernandezpintoalberto insulinreceptoractivationbyproinsulinpreservessynapsesandvisioninretinitispigmentosa
AT lilloconcepcion insulinreceptoractivationbyproinsulinpreservessynapsesandvisioninretinitispigmentosa
AT isiegascarolina insulinreceptoractivationbyproinsulinpreservessynapsesandvisioninretinitispigmentosa
AT marchenamiguel insulinreceptoractivationbyproinsulinpreservessynapsesandvisioninretinitispigmentosa
AT lizasoainignacio insulinreceptoractivationbyproinsulinpreservessynapsesandvisioninretinitispigmentosa
AT boschfatima insulinreceptoractivationbyproinsulinpreservessynapsesandvisioninretinitispigmentosa
AT delavillapedro insulinreceptoractivationbyproinsulinpreservessynapsesandvisioninretinitispigmentosa
AT hernandezsanchezcatalina insulinreceptoractivationbyproinsulinpreservessynapsesandvisioninretinitispigmentosa
AT delarosaenriquej insulinreceptoractivationbyproinsulinpreservessynapsesandvisioninretinitispigmentosa